TNP-470 inhibits 7,12-dimethylbenz[a]anthracene-induced mammary tumor formation when administered before the formation of carcinoma in situ but is not additive with tamoxifen

Lab Invest. 2003 Jul;83(7):1001-11. doi: 10.1097/01.lab.0000075641.27128.67.

Abstract

In many women pathologic lesions, such as hyperplasia and carcinoma in situ, precede invasive breast cancer. We have shown that tissue vascularity increases with histologic progression to invasive disease. Similarly, in the well-characterized 7,12-dimethylbenz[a]anthracene (DMBA) model of mammary tumorigenesis, preinvasive lesions exhibit increased vascularity with progression. Using this model we asked whether inhibition of angiogenesis would block progression and if so, at which stage. We treated rats with DMBA followed by the potent angiogenic inhibitor, TNP-470, and/or tamoxifen starting 1 day or 6 weeks later. Histopathology and in vitro angiogenic potential of mammary organoids were evaluated 3 months after DMBA. All statistical tests were two-sided. Early TNP-470 and tamoxifen treatment inhibited the formation of carcinoma in situ (p < 0.001) and invasive disease (p < 0.001). However, their effects were not additive, despite their unique mechanisms of action. TNP-470 administration begun at the time of microscopic carcinoma in situ formation was unable to prevent the further development of carcinoma in situ or invasive breast cancer, whereas tamoxifen was highly effective (p = 0.001). There was no added benefit of combining TNP-470 and tamoxifen. TNP-470 therapy, unlike tamoxifen, did not inhibit the angiogenic potential of DMBA-treated normal mammary organoids, supporting its lack of a direct effect on the epithelium. These data provide proof-in-principle that inhibition of angiogenesis early in mammary tumorigenesis prevents mammary tumor formation in a hormone-sensitive model, indicating that angiogenesis is a potential target for cancer chemoprevention. Interactions with other chemopreventive strategies and the timing of administration must be thoroughly examined in vivo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antibiotics, Antineoplastic / therapeutic use*
  • Carcinogens / toxicity
  • Carcinoma in Situ / blood supply
  • Carcinoma in Situ / pathology
  • Carcinoma in Situ / prevention & control*
  • Carcinoma, Intraductal, Noninfiltrating / blood supply
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Carcinoma, Intraductal, Noninfiltrating / prevention & control*
  • Cyclohexanes
  • Disease Models, Animal
  • Drug Interactions
  • Female
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control*
  • Neovascularization, Pathologic
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Precancerous Conditions / blood supply
  • Precancerous Conditions / pathology
  • Precancerous Conditions / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Sesquiterpenes / therapeutic use*
  • Tamoxifen / therapeutic use*

Substances

  • Angiogenesis Inhibitors
  • Antibiotics, Antineoplastic
  • Carcinogens
  • Cyclohexanes
  • Sesquiterpenes
  • Tamoxifen
  • 9,10-Dimethyl-1,2-benzanthracene
  • O-(Chloroacetylcarbamoyl)fumagillol